Synthesis of [13C] and [2H] substituted methacrylic acid, [13c] and [2H] substituted methyl methacrylate and/ or related compounds

ABSTRACT

The present invention is directed to labeled compounds of the formulae  
                 
 
wherein Q is selected from the group consisting of —S—, —S(═O)—, and —S(═O) 2 —, Z is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure  
                 
 
wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, a C 1 -C 4  lower alkyl, a halogen, and an amino group selected from the group consisting of NH 2 , NHR and NRR′ where R and R′ are each independently selected from the group consisting of a C 1 -C 4  lower alkyl, an aryl, and an alkoxy group, and X is selected from the group consisting of hydrogen, a C 1 -C 4  lower alkyl group, and a fully-deuterated C 1 -C 4  lower alkyl group. The present invention is also directed to a process of preparing labeled compounds, e.g., process of preparing [ 13 C]methacrylic acid by reacting a (CH 3 CH 2 O— 13 C(O)— 13 CH 2 )—aryl sulfone precursor with  13 CHI to form a (CH 3 CH 2 O— 13 C(O)— 13 C( 13 CH 3 ) 2 )—aryl sulfone intermediate, and, reacting the (CH 3 CH 2 O— 13 C(O)— 13 C( 13 CH 3 ) 2 )—aryl sulfone intermediate with sodium hydroxide, followed by acid to form [ 13 C]methacrylic acid. The present invention is further directed to a process of preparing [ 2 H 8 ]methyl methacrylate by reacting a (HOOC—C(C 2 H 3 ) 2 —aryl sulfinyl intermediate with CD 3 I to form a ( 2 H 3 COOC—C(C 2 H 3 ) 2 )—aryl sulfinyl intermediate, and heating the ( 2 H 3 COOC—C(C 2 H 3 ) 2 )—aryl sulfinyl intermediate at temperatures and for time sufficient to form [ 2 H 8 ]methyl methacrylate.

STATEMENT REGARDING FEDERAL RIGHTS

This invention was made with government support under Contract No.W-7405-ENG-36 awarded by the U.S. Department of Energy. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to labeled compounds and more particularlyto compounds labeled with carbon-13 and hydrogen-2. More particularly,the present invention relates intermediates useful in the preparation of[¹³C₁₋₅]methacrylic acid, [¹³C₁₋₅, ²H₅]methacrylic acid,[²H₅]methacrylic acid, [¹³C₁₋₅]methyl methacrylate, [¹³C₁₋₅, ²H₅]methylmethacrylate, [¹³ C₁₋₆, ²H₈]methyl methacrylate, [²H₅]methylmethacrylate, [²H₈]methyl methacrylate, and the like.

BACKGROUND OF THE INVENTION

The use of fully deuterated methacrylic acid for preparation ofpolyacrylic acid and subsequent preparation of optical fibers from suchpolyacrylic acid has been demonstrated to give an enhancement in thetransmission distances of the optical fibers. Hence, a cost effectivemethod for the production of large quantities of deuterated methacrylicacid is desirable. Currently, the starting material of [² H₅]methacrylicacid is produced from [²H₆]acetone and cyanide. The [²H₆]acetone isproduced by exchange with deuterium oxide which makes the production oflarge quantities of that material extremely expensive.

The development of alternative routes for the production of[²H₅]methacrylic acid from D₂ could lower the costs. Additionally, thedevelopment of routes for the production of [²H₈] methyl methacrylate isdesirable.

SUMMARY OF THE INVENTION

In accordance with the purposes of the present invention, as embodiedand broadly described herein, the present invention provides selectedlabeled compounds of the formulae

wherein Q is selected from the group consisting of —S—, —S(═O)—, and—S(═O)₂—, Z is selected from the group consisting of 1-naphthyl,substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenylgroups with the structure

wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from thegroup consisting of hydrogen, a C₁-C₄ lower alkyl, a halogen, and anamino group selected from the group consisting of NH₂, NHR and NRR′0where R and R′ are each independently selected from the group consistingof a C₁-C₄ lower alkyl, an aryl, and an alkoxy group, and X is selectedfrom the group consisting of hydrogen, a C₁-C₄ lower alkyl group, and afully-deuterated C₁-C₄ lower alkyl group. In one preferred embodiment, Xis methyl.

The present invention further provides a process of preparing[¹³C]methacrylic acid by reacting a (CH₃CH₂O—¹³C(O)—¹³CH₂)—aryl sulfoneprecursor with ¹³CHI to form a (CH₃CH₂O—¹³C(O)—¹³C(¹³CH₃)₂)—aryl sulfoneintermediate; and, reacting the (CH₃CH₂O—¹³C(O)—¹³C(¹³CH₃)₂)—arylsulfone intermediate with sodium hydroxide, followed by reaction with anacid such as hydrochloric acid to form [¹³C]methacrylic acid.

The present invention further provides a process of preparing[²H₈]methyl methacrylate by reacting a (HOOC—C(C²H₃)₂—aryl sulfinylintermediate with CD₃I to form a (²H₃COOC—C(C²H₃)2)—aryl sulfinylintermediate, and heating the (²H₃COOC—C(C²H₃)₂)—aryl sulfinylintermediate at temperatures and for time sufficient to form [²H₈]methylmethacrylate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a synthetic route to 2-[²H₃]methyl-2-propenoic[3,3-²H₂]acid, —[²H₃]methyl ester (or [²H₈]methyl methacrylate) throughthe intermediate compounds of diethyl [²H₆]dimethylmalonate,[3,3,3,3′,3′,3′-²H₆]isobutyric acid,2-[²H₃]methyl-2-(phenylthio)-[3,3,3-²H₃]propionoic acid,2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionoic acid, and2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionoic acid [²H₃]methylester.

FIG. 2 shows two synthetic routes to phenylthio-[1,2-¹³C₂]acetic acidfrom either [¹³C]methyl phenyl sulfide and ¹³C]carbon dioxide or frombromo-[1,2-¹³C₂]acetic acid. In addition FIG. 2 shows the conversion ofphenylthio-[1,2-¹³C₂]acetic acid to phenylsulfinyl-[1,2-¹³C₂]acetic acidand phenylsulfonyl-[1,2-¹³C₂]acetic acid.

FIG. 3 shows a synthetic route to ethyl2-[¹³C]methyl-2-(phenylsulfonyl)-[1,2,3-¹³C₃]propionate which couldserve as a precursor to [¹³C₅]methacrylic acid. This reaction sequenceinvolves the intermediates phenylthio-[1,2-¹³C₂]acetic acid, ethylphenylthio-[1,2-¹³C₂]acetate, and ethyl(phenylsulfonyl)-[1,2-¹³C₃]acetate.

FIG. 4 shows a synthetic route to ethyl2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate which couldserve as a precursor to Ethyl [¹³C₅]methacrylate(2-[¹³C]methyl-2-[1,2,3-¹³C₃]propenoic acid ethyl ester). This reactionsequence involves the intermediates phenylthio-[1,2-¹³C₂]acetic acid,ethyl phenylthio-[1,2-¹³C₂]acetate, ethyl(phenylsulfinyl)-[1,2-¹³C₃]acetate, and ethyl2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate

DETAILED DESCRIPTION

The present invention is concerned with various labeled compounds, andespecially to certain labeled methylacrylic acids and methylmethacrylates. Further, the present invention is concerned withprocesses of preparing such labeled compounds.

As used herein, the term “aryl” means a monovalent monocyclic orbicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, andoptionally substituted independently with one, two, three, four or fivesubstituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro,cyano, —OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,optionally substituted phenyl), acyl, and —COOR (where R is hydrogen oralkyl). More specifically, the term “aryl” includes, but is not limitedto 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted2-naphthyl, and phenyl groups with the structure

wherein R₁, R₂, R₃, R₄ and R₅ are each independently hydrogen, a loweralkyl, i.e., a C₁-C₄ alkyl such as methyl, ethyl, n-propyl, iso-propyl,butyl, isobutyl, and tert-butyl, a halogen such as chloro, bromo oriodo, an amino group such as NH₂, NHR or NRR′ where R and R′ are eachindependently a lower alkyl or an aryl as described above, or an alkoxygroup such as O-alkyl or O-aryl where the alkyl is a lower alkyl asdescribed above or an aryl as described above. By “substituted” is meantthat the naphthyl group can include one or more substituents in place ofa hydrogen atom, such substituents including the same as described forR₁-R₅.

As used herein, the term “[¹³C, ²H_(n)]” means the particular compoundincludes a ¹³C label and deuterium atoms in place of n number ofhydrogens. The present invention provides a process of preparing labeledcompounds as described wherein the resultant product includes one ormore of the desired labels, i.e., ¹³C and/or ²H, at an abundance leveldetectably greater than its natural abundance. Similarly, the labeledcompounds of the present invention include one or more of the desiredlabels, i.e., ¹³C and/or ²H, at an abundance level detectably greaterthan its natural abundance.

The present invention provides labeled compounds of the formulae

wherein Q is selected from the group consisting of —S—, —S(═O)—, and—S(═O)₂—, Z is an aryl group selected from the group consisting of1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl,and phenyl groups with the structure

wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from thegroup consisting of hydrogen, a C₁-C₄ lower alkyl, a halogen, and anamino group selected from the group consisting of NH₂, NHR and NRR′where R and R′ are each independently selected from the group consistingof a C₁-C₄ lower alkyl, an aryl, and an alkoxy group, and X is selectedfrom the group consisting of hydrogen, a C₁-C₄ lower alkyl group, and afully-deuterated C₁-C₄ lower alkyl group. Such labeled materials can beattractive for a variety of applications, especially for the preparationof 2-[²H₃]methyl-2-propenoic-[3,3-²H₂] acid [²H₃]methyl-ester (sometimesknown as [²H₈]methyl methacrylate or [²H₃]methyl [²H₅]methacrylate) andfor the preparation of 2-[²H₃]methyl-2-propenoic-[3,3-²H₂] acid(sometimes known as [²H₅]methacrylic acid). These deuterated methacrylicacid and deuterated methyl methacrylate are useful in the preparation ofdeuterated polyacrylates. Further, [¹³C, ²H₈]- and [²H₈]-labeledmaterials can be attractive for application in metabolism studies andfor mass tagging of polymers and monomers. Various combinations of ¹³Cand ²H labeling can be accomplished by the teachings of the presentinvention.

Throughout the present description, the group referred to as sulfide(also referred to as thio) can also be represented by —S—. The groupreferred to as sulfinyl can also be represented by —S(═O)—. The groupreferred to as sulfone can also be represented by —S(═O)₂—. Generally,where one of the particular sulfur groups is described, such as sulfide,the processes may be carried out with the other sulfur groups, such assulfinyl or sulfone.

The present invention also provides efficient processes for thepreparation of virtually any ²H and/or ¹³C containing isotopomers ofmethacrylic acid and methyl methacrylate.

In one embodiment, a process of preparing [²H₈]methyl methacrylateincludes reacting a (HOOC—C(C²H₃)₂—aryl sulfinyl intermediate with CD₃Ito form a (²H₃COOC—C(C²H₃)₂)—aryl sulfinyl intermediate, and heating the(²H₃COOC—C(C²H₃)₂)—aryl sulfinyl intermediate at temperatures and fortime sufficient to form [²H₈]methyl methacrylate

The present invention is more particularly described in the followingexamples, which are intended as illustrative only, since numerousmodifications and variations will be apparent to those skilled in theart.

EXAMPLE 1

Synthesis of diethyl [²H₆]dimethylmalonate (compound 2 in FIG. 1) was asfollows. Diethyl malonate (10 g, 0.0624 moles) was dissolved intodimethylformamide (DMF) (120 mL) and to this solution, potassiumcarbonate (25.9 g, 0.1873 moles) was added. The reaction was stirred atroom temperature for 1 hour and then [²H₃]methyl iodide (18.2 g, 0.128moles) was added to the mixture. The reaction was stirred for 4 days andthen filtered to remove the excess potassium carbonate and potassiumiodide. The red DMF solution was then treated with aqueous sodiumthiosulfate (5% by wt) (100 mL). This solution was extracted withportions of ethyl acetate (3×250 mL) and the ethyl acetate layer wasdried over sodium sulfate. The solvent was removed and a 1:1 mixture ofthe diethyl [²H₆]dimethylmalonate and DMF was isolated. The yield wascalculated (by NMR) to be 92%.

Synthesis of [3,3,3,3′,3′,3′-²H₆]isobutyricacid (compound 3 in FIG. 1)was as follows. The 1:1 mixture of diethyl [²H₆]dimethylmalonate(compound 2 in FIG. 1) was suspended into hydrochloric acid (12N, 75 mL)and heated to reflux for 24 hours. After this period the reaction wasdiluted into 75 mL of water and then extracted with portions ofdichloromethane (4×100 mL). The organic layer was then dried over sodiumsulfate and evaporated to give 2.3 g of the[3,3,3,3′,3′,3′-²H₆]isobutyric acid.

Synthesis of 2-[²H₃]methyl-2-(phenylthio)-[3,3,3-²H₃]propionoic acid,(compound 4 in FIG. 1) was as follows. [3,3,3,3′,3′,3′-²H₆]Isobutyricacid (9.72 g, 0.1033 moles) was dissolved into tetrahydrofuran (THF)(200 mL) and cooled in an ice bath. To this mixture, lithium diisopropylamide (1.5M, 151 mL, 0.2272 moles) was added slowly. After 30 minutes,diphenyl disulfide (24.81 g, 0.1136 moles) was added as a solution inTHF (100 mL). The reaction was allowed to warm to room temperature andthen stirred overnight. The reaction mixture was poured into water (300mL) and then extracted with portions of ethyl acetate (3×100 mL). The pHof the aqueous solution was adjusted to pH=7.5 with hydrochloric acid(1M) and then extracted again with portions of ethyl acetate (3×100 mL).The pH of the aqueous was then adjusted to 2.5 with hydrochloric acid(1N) and extracted with portions of ethyl acetate (3×150 mL). Theorganic layer was dried with sodium sulfate and then evaporated to give19.01 g (91%) of the 2-[²H₃]methyl-2-(phenylthio)-[3,3,3-²H₃]propionoicacid. The product was suitable for use in the next step withoutpurification.

Synthesis of 2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionoicacid, (compound 5 in FIG. 1) was as follows.2-[²H₃]methyl-2-(phenylthio)-[3,3,3-²H]propionoic acid, (compound 4 inFIG. 1) (2.5 g, 0.0127 moles) was dissolved into methanol:water (1:1 v/v37.5 mL) and to this mixture sodium periodate (3.00 g, 0.014 moles) wasadd as a solid. The reaction was stirred for 3 hours at room temperatureand then filtered to remove solids. The solution was evaporated toremove most of the methanol and then extracted with portions ofdichloromethane (4×100 mL). The organic layer was dried and evaporatedto yield the [3,3,3-²H₃]propionic acid,2-[²H₃]methyl-2-(phenylsulfinyl)—(2.5 g 92%). The product was suitablefor use in the next step without purification.

Synthesis of 2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionoicacid, methyl ester (compound 6 in FIG. 1) was as follows.2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]Propionic acid, (12 g, 0.059moles) was dissolved into dimethylformamide (24 mL). Potassium carbonate(8.98 g, 0.065 moles) was added to the reaction. The mixture was allowedto stir for 15 minutes and then [²H₃]methyl iodide (2.29 g, 0.065 moles)was added neat. The reaction was stirred for 1 hour and then quenchedwith hydrochloric acid (1N, 20 mL). The reaction was extracted withportions of dichloromethane (3×50 mL) and then the organic was driedover sodium sulfate then evaporated to give a yellow oil which containedonly a trace of DMF and pure product. The DMF was removed by vacuum at50° C. which left only the pure2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionic acid, methyl ester(12.99 g, 99.8%) which was suitable for use in the next step withoutpurification.

Synthesis of 2-[²H₃]methyl-2-[3,3-²H₂]propenoic acid [²H₃]methyl ester(compound 7 in FIG. 1) was as follows. The solid2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionic acid methyl ester(5 g, 0.021 moles) was slowly heated to 100° C. under vacuum and the2-[²H₃]methyl-2-[3,3-²H₂]propenoic-acid [²H₃]methyl ester was collectedby using a dry ice trap. The reaction was heated until the productstopped distilling over. The product (2.15 g, 93%) containedapproximately 2 percent water. This water was removed by distillationfrom calcium hydride. The yield after this step was 85%.

EXAMPLE 2

The synthesis of phenylthio-[1,2-¹³C₂]acetic acid (compound 9 in FIG. 2)was as follows. A round-bottomed flask (1000 ml) was equipped with arubber septum and a magnetic stir bar and placed under an argonatmosphere. In the flask, the [1-¹³C]methyl phenyl sulfide (compound 8in FIG. 2) (30.0 g, 0.240 mol) was dissolved in freshly distilledtetrahydrofuran (450 ml). The flask was cooled to −78° C. with a dryice/ethanol bath. To this solution, sec-butyllithium (188 ml, 0.264 mol)was added drop wise over 10 minutes. The solution was stirred for 30 minat −78° C. The ¹³CO₂ (5.4 g, 0.120 mol) was placed in a stainless steellecture bottle (250 ml) which was attached to the pressure/vacuummanifold. The reaction flask was attached to the manifold and evacuated.¹³CO₂ was introduced into the reaction vessel over a few minutes so thatthe pressure in the flask does not exceed 760 mm. After the addition ofthe ¹³CO₂, the reaction was stirred for 1 hr at −78° C. then stirringwas continued as the reaction was allowed to warm to room temperature (2hrs). The reaction was quenched with the addition of water (100 ml), theaqueous layer was extracted with portions of ethyl acetate (3×100 ml).Then pH of the aqueous layer was then acidified using an aqueoussolution of hydrochloric acid (6N) to pH 2.0. The aqueous layer was thenextracted with portions of ethyl acetate (3×200 ml). The organic layerwas dried with solid sodium sulfate and the solvent removed in vacuo.Volatile compounds were removed from the resulting oil under vacuumed.The resulting yellowish solid was phenylthio-[1,2-¹³C]acetic acid (18.95g, 93%).

Alternatively, phenylthio-[1,2-¹³C₂]acetic acid (compound 9 in FIG. 2)was prepared from bromo-[1,2-¹³C₂]acetic acid (compound 12 in FIG. 2). Aseparate round-bottom flask was charged with a solution containing NaOH(1.56 g, 0.039 moles), H₂O (50 ml) and ethanol. The flask was sealedwith a rubber septum and stirred at room temperature. The benzenethiol(4.29 g, 0.039 moles) was then added via syringe to the NaOH/ethanolsolution and this allowed stirring for approximately 30 min. A solutioncontaining bromo-[1,2-¹³C₂]acetic acid (5 g, 0.035 moles), H₂O (50 ml),and sodium bicarbonate (3.27 g, 0.039 moles) was then added to thebenzenethiol solution and the combined solution stirred for 1 hr. Thesolution was acidified with 6M HCl to pH=2.0 and extracted with portionsof ethylacetate (3×200 ml). The combined organic layers were dried oversodium sulfate, filtered and solvent removed by rotary evaporation.Purification by chromatography on silica gel yieldedphenylthio-[1,2-¹³C₂]acetic acid (compound 9 in FIG. 2) (4.87 g, 82%).

EXAMPLE 3

The synthesis of ethyl phenylthio-[1,2-¹³C₂]acetate (compound 14 in FIG.3) was as follows. A round-bottom flask (500 ml) was fixed with acondenser cooled to 4° C. The flask was charged with a solution ofphenylthio-[1,2-¹³C₂]acetic acid (16.32 g, 0.096 mol), in dry ethanol(200 ml). Amberlyst®15 ion-exchange to the solution (7.0 g). Thesuspension was stirred using magnetic stirrer while heating to reflux(94° C.). The suspension was allowed to reflux for 6 hrs before cooling.When the solution has thoroughly cooled, the Amberlyst® was filtered offand the ethanol removed using a rotary evaporator. Extraction of theaqueous layer with portions of ethyl acetate (3×200 ml) and removal ofthe solvent (rotary evaporation) gave ethyl phenylthio-[1,2-¹³C₂]acetate(14.73 g, 78%) as a brown viscous liquid.

Synthesis of ethyl (phenylsulfonyl)-[1,2-¹³C₃]acetate (compound 15 inFIG. 3) was as follows. Oxone® (potassium peroxymonosulfate) (307 g,0.255 moles) was dissolved in water (500 mL). Ethyl2-(phenylthio)-[1,2-¹³C₂]acetate (16.63 g, 0.085 moles) was dissolved ina mixture of ethyl acetate (100 mL) and ethanol (100 mL). This solutionwas added dropwise to the Oxone® solution over an hour. After theaddition was complete, the reaction was stirred for an additional hour.The solution was then evaporated to remove most of the organic solvents.The aqueous layer was then extracted with portions of ethyl acetate(4×200 mL). The organic layer was dried over sodium sulfate, filteredand evaporated to give a quantitative yield of the ethyl(phenylsulfonyl)-[1,2-¹³C₂]acetate (compound 15 in FIG. 3)

The synthesis of ethyl2-[¹³C]methyl-2-(phenylsulfonyl)-[1,2,3-¹³C₂]propionate (compound 16 inFIG. 3) was as follows. Ethyl phenylsulfonyl-[1,2-¹³C₂]acetate (0.5 g,0.00217 moles) was suspended in dimethylformamide (15 ml) and allowed tostir for 15 m at room temperature. Solid potassium carbonate was addedto the solution and allowed to stir for 1 hr at room temperature. Then[¹³C]methyl iodide (0.713 g, 0.005 moles) was added to the solution. Theround bottom flask capped tightly with a Teflon® stopper, and thereaction was allowed to proceed overnight. The product was isolated byfiltering to remove the potassium carbonate precipitate. The filtratewas extracted with portions of ethyl acetate (3×50 ml). The combinedorganic layers were dried with sodium sulfate and the solvents removedby rotary evaporation. Residual DMF was removed in vacuo at 35-40° C.Ethyl 2-[¹³C]methyl-2-(phenylsulfonyl)-[1,2,3-¹³C₃]propionate wasrecovered as slightly yellow oil (0.46 g, 82%).

As diagrammed in FIG. 3, ethyl2-[¹³C]methyl-2-(phenylsulfonyl)-[1,2,3-¹³C₃]propionate could serve as aprecursor to [¹³C₅]methacrylic acid.

EXAMPLE 4

The synthesis of ethyl phenylthio-[1,2-¹³C₂]acetate (compound 19 in FIG.4) was as described in Example 3. Ethyl phenylsulfinyl-[1,2-¹³C₂]acetate(compound 20 in FIG. 4) was prepared as follows. A 500 ml round-bottomflask was charged with a solution that contained ethylphenylthio-[1,2-¹³C₂]acetate (10 g, 0.0505 moles) and 100 ml of a 50:50mixture of methanol:H₂O and was stirred using a magnetic stirrer. Sodiumperiodate (12.96 g, 0.0606 moles) was added to the solution and thereaction was stirred at room temperature for 24 h. The reaction mixturewas then filtered to remove a white precipitate and methanol was removedfrom the filtrate using a rotary evaporator. The aqueous solution wasextracted with portions of ethyl acetate (3×200 ml). The organic layerwas dried over sodium sulfate, filtered and the solvent removed byrotary evaporation. Ethyl phenylsulfinyl-[1,2-¹³C₂]acetate (compound 20in FIG. 4) was recovered as a colorless oil (10.74 g, 99%).

Ethyl 2-phenylsulfinyl-[1,2,3-¹³C₃]propionate (compound 21 in FIG. 4)was prepared as follows. A round bottom flask (250 ml) was charged withsolution containing ethyl phenylsulfinyl-[1,2-¹³C₂]acetate (5.0 g,0.0233 mol), dissolved in dry tetrahydrofuran, and the solution wasstirred under an argon atmosphere. The flask was cooled to −78° C. witha dry ice/ethanol bath. To the cooled solution, lithium diisopropylamineas a 1.5 M solution in cyclohexane (17.3 ml, 0.0257 mol) was added dropwise over 5 minutes. The reaction mixture was continually stirred at−78° C. for 1 hr. Then ¹³CH₃I (3.50 g, 0.0245 mol) was added to theflask with a syringe and again the reaction was allowed to stir at −78°C. for 1 hr. Then the reaction was allowed to warm to room temperatureand stirred for an additional 2 hrs. The reaction was quenched with theaddition of a saturated ammonium chloride solution (50 ml). An aqueoussolution of sodium thiosulfate was then added to consume residual CH₃I.The organic layer was extracted with portions of ethyl acetate (2×200ml) and the ethyl acetate layer was washed with distilled water toremove ammonium chloride. The ethyl acetate layer was then dried oversolid sodium sulfate, filtered and the solvent removed by rotaryevaporation. The extraction gave ethyl2-phenylsulfinyl-[1,2,3-¹³C₃]propionate (compound 21 in FIG. 4) (5.44 g,102%) as a clear-yellowish liquid.

Ethyl 2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate, (compound22 in FIG. 4) was prepared as follows. A round bottom flask (250 ml) wascharged with a solution containing ethyl2-phenylsulfinyl-[1,2,3-¹³C₃]propionate (1.5 g, 0.0065 moles) andfreshly distilled tetrahydrofuran (22.5 ml). The solution was stirredwith a magnetic stirrer placed under an argon atmosphere and cooled to−78° C. with a dry ice/ethanol bath. Using a syringe, lithiumdiisopropylamine as a 1.5 M solution in cyclohexane (4.8 ml, 0.00.0072moles) was added drop wise over 5 minutes. After stirring the solutionat −78° C. for 30 min, ¹³CH₃I (0.983 g, 0.0069 mol) was added to theflask via syringe. The reaction was allowed to stir at −78° C. for 1 hrand then allowed to warm to room temperature. After stirring for anadditional 2 hrs, the reaction was quenched with the addition of asaturated ammonium chloride solution (15 ml). An aqueous solution ofsodium thiosulfate was then added to consume residual CH₃I. The organiclayer was extracted with portions of ethyl acetate (2×200 ml) and theethyl acetate layer was washed with distilled water to remove ammoniumchloride. The ethyl acetate layer was then dried over solid sodiumsulfate, filtered and the solvent removed by rotary evaporation. Theextraction of the aqueous layer gave ethyl(1,2,3,4-¹³C₄)-thiophenylbutanoate sulfoxide (1.59 g, 103%) to aclear-yellowish liquid. The extraction gave ethyl2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate, (compound 22 inFIG. 4) as a clear-yellowish liquid (5.44 g, 102%).

Ethyl [¹³C₅]methacrylate (2-[¹³C]methyl-2-[1,2,3-¹³C₃]propenoic acidethyl ester) is preparable from ethyl2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate (compound 22 inFIG. 4) in the manner described for the deuterated isotopomer (compound7 in FIG. 1) of Example 1, i.e., by heating at a suitable temperatureand pressure.

Although the present invention has been described with reference tospecific details, it is not intended that such details should beregarded as limitations upon the scope of the invention, except as andto the extent that they are included in the accompanying claims.

1. A labeled compound of the formulae

wherein Q is selected from the group consisting of —S—, —S(═O)—, and—S(═O)₂—, Z is an aryl group selected from the group consisting of1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl,and phenyl groups with the structure

wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from thegroup consisting of hydrogen, a C₁-C₄ lower alkyl, a halogen, and anamino group selected from the group consisting of NH₂, NHR and NRR′where R and R′ are each independently selected from the group consistingof a C₁-C₄ lower alkyl, an aryl group, and an alkoxy group, and X isselected from the group consisting of hydrogen, a C₁-C₄ lower alkylgroup, and a fully-deuterated C₁-C₄ lower alkyl group.
 2. The labeledcompound of claim 1 wherein Q is —S— and X is hydrogen.
 3. The labeledcompound of claim 1 wherein Q is —S(═O)— and X is hydrogen.
 4. Thelabeled compound of claim 1 wherein Q is —S(═O)₂— and X is hydrogen. 5.The labeled compound of claim 1 wherein Q is —S(═O)— and X is C²H₃. 6.The labeled compound of claim 2 wherein the labeled compound is2-[²H₃]methyl-2-(phenylthio)-[3,3,3-²H₃]propionoic acid.
 7. The labeledcompound of claim 2 wherein the labeled compound isphenylthio-[1,2-¹³C₂]acetic acid.
 8. The labeled compound of claim 3wherein the labeled compound is phenylsulfinyl-[1,2-¹³C₂]acetic acid. 9.The labeled compound of claim 4 wherein the labeled compound isphenylsulfonyl-[1,2-¹³C₂]acetic acid.
 10. The labeled compound of claim1 wherein the labeled compound is ethyl phenylthio-[1,2-¹³C₂]acetate.11. The labeled compound of claim 1 wherein the labeled compound isethyl (phenylsulfonyl)-[1,2-¹³C₂]acetate.
 12. The labeled compound ofclaim 5 wherein the labeled compound is2-[²H₃]methyl-2-(phenylsulfinyl)-[3,3,3-²H₃]propionoic acid, methylester.
 13. The labeled compound of claim 1 wherein the labeled compoundis ethyl 2-[¹³C]methyl-2-(phenylsulfonyl)-[1,2,3-¹³C₂]propionate. 14.The labeled compound of claim 1 wherein the labeled compound is ethylphenylsulfinyl-[1,2-¹³C₂]acetate.
 15. The labeled compound of claim 1wherein the labeled compound is ethyl2-phenylsulfinyl-[1,2,3-¹³C₃]propionate.
 16. The labeled compound ofclaim 1 wherein the labeled compound is ethyl2-[¹³C]methyl-2-(phenylsulfinyl)-[1,2,3-¹³C₃]propionate.
 17. A processof preparing [¹³C]methacrylic acid comprising: reacting a(CH₃CH₂O—¹³C(O)—¹³CH₂)—aryl sulfone precursor with ¹³CHI to form a(CH₃CH₂O—¹³C(O)—¹³C(¹³CH₃)₂)—aryl sulfone intermediate; and, reactingthe (CH₃CH₂O—¹³C(O)—¹³C(¹³CH₃)₂)—aryl sulfone intermediate first withsodium hydroxide and then with hydrochloric acid to form[¹³C]methacrylic acid.
 18. A process of preparing [²H₈]methylmethacrylate comprising: reacting an aryl sulfinyl intermediate withdeuterated methyl iodide to form a [²H₉] aryl sulfide intermediate; and,heating the [²H₉] aryl sulfide intermediate at temperatures and for timesufficient to form [²H₈]methyl methacrylate.